1. Field of the invention
This invention relates to methods and compositions for inhibiting post-surgical adhesions in the mammalian abdominal or thoracic cavity or other body spaces, whether accidentally or surgically created.
2. Description of the Prior Art
There is a need for improved methods and compositions for inhibiting adhesion formation/reformation in body spaces of mammals, whether accidentally or surgically created. According to Ellis in a review entitled, "The Cause And Prevention of Post-operative Intraperitoneal Adhesions," in Surgery, Gynecology and Obstetrics for September 1971, volume 133, pages 497-509, at pages 502-503, the prevention of adhesions has been the subject of an enormous amount of work since the beginning of this century. According to Ellis, these attempts have included means of preventing the fibrin-coated walls of the intestine from reaching each other by distending the abdomen with oxygen or filling the abdomen with saline solution, paraffin, olive oil, lanolin, concentrated dextrose solution, macromolecular solutions of all sorts, and silicones.
Menzies and Ellis in a review entitled, "Intestinal Obstruction from Adhesions--How Big is the Problem?" Annals of the Royal College of Surgeons of England, vol 72 pages 60-63, 1990 reported finding adhesions in 10.4% of 115 patients with first-time laparotomies while 93% of 210 patients had intra-abdominal adhesions due to previous surgery. Admission for intestinal obstruction was made for 0.9% of 28,297 general surgery patients while 3.3% of 4,502 laparotomy patients were admitted for intestinal obstruction due to adhesions. These data emphasize the magnitude of readhesions after adhesiolysis or from subsequent surgical procedures. The authors state on p. 62, that there is currently no effective treatment that prevents their recurrence.
High molecular weight dextran either alone or in combination with dextrose has been used to prevent peritoneal adhesions subsequent to surgery. Dextran is clinically standardized to a low molecular weight of about 75,000 by partial hydrolysis and factional precipitation of the high molecular weight particles which normally have molecular weights up to 200,000. Dextran is a polymer of glucose which has a chain-like structure and is produced from sucrose by Lenconostoc bacteria. In articles appearing in Fertility and Sterility, volume 33, number 6, June 1980, pages 660-662, Holtz, Baker, and Tsai and volume 34, number 4, October, 1980, pages 394-395, by Holtz and Baker, results are reported of the adhesion reducing effects of a 32% (aqueous) solution of Dextran 70 containing 10% dextrose (sold under the trade name HYSKON by Pharmacia, of Piscataway, N.J.). Holtz et al postulate several mechanisms of action in the prevention of peritoneal adhesions utilizing HYSKON.RTM. including a simple mechanical separation of adjacent surfaces, termed a hydroflotation effect.
Project coordinator diZerega and several contributors have reported the results of a large study in an article entitled, "Reduction of Post-operative Pelvic Adhesions with Intraperitoneal 32% Dextran 70: A Prospective, Randomized Clinical Trial," in Fertility and Sterility, volume 40, number 5, for November 1983, pages 612-619. The authors, on page 618, indicate that the use of Dextran intraperitoneally has limitations such as the reported tendency of HYSKON to support bacterial proliferation and concern over the anaphylactoid potential of dextran. In addition, the benefit of Dextran 70 in preventing post-operative adhesions was shown to be limited to the lower regions of the pelvis.
Borten, Seibert, and Taymor in Obsterics and Gynecology, vol 61, number Jun., 6, 1983, pages 755-757 report in an article entitled, "Recurrent Anaphylactic Reaction to Intraperitoneal Dextran 75 Used for Prevention of Postsugical Adhesions". These authors indicate that anaphylactic reaction to Dextran administered intravenously is well documented and report such a reaction after intraperitoneal administration of Dextran.
The use of ethylene oxide/propylene oxide block copolymers as surfactants in surgical scrub solutions and the topical application of 10% solutions of these copolymers to wounds is described in Edlich et al in the Journal of Surgical Research, volume 14, number 4, April 1973, pages 277-284. The test results indicate that copolymers having an ethylene oxide:propylene oxide ratio of 4:1 provide less inflammatory response in a wound to which the copolymer is applied in comparison with a copolymer having an ethylene oxide:propylene oxide ratio of 1:4. There is no indication by Edlich et al or any cited prior art that such copolymers are useful in reducing postoperative adhesions or that isotonic, aqueous solutions of such copolymers are useful in reducing post-operative adhesions.
Over the years, methods have been developed to achieve the efficient delivery of a therapeutic drug to a mammalian body part requiring pharmaceutical treatment. Use of an aqueous composition which can be applied at room temperature as a liquid but which forms a semi solid gel when warmed to body temperature has been utilized as a vehicle for drug delivery. Such a system combines ease of application with greater retention at the site requiring treatment than would be the case if the aqueous composition were not converted to a gel as it is warmed to mammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are used in aqueous compositions to provide thermally gelling aqueous systems. Adjusting the concentration of the polymer, provides the desired sol-gel transition, that is, the lower the concentration of polymer, the higher the sol-gel transition temperature.
In U.S. Pat. Nos. 4,474,751; 752; 753; and 4,478,822, drug delivery systems are described which utilize thermosetting polyoxyalkylene gels; the unique feature of these systems is that both the gel transition temperature and/or the rigidity of the gel can be modified by adjustment of the ionic strength, as well as by the concentration of the polymer.
Other patents disclosing pharmaceutical compositions which rely upon an aqueous gel composition as a vehicle for the application of the drug or cosmetic preparation are U.S. Pat. Nos. 4,883,660; 4,861,760; 4,810,503; 4,767,619; and 4,511,563.
Steinleitner et al in an article entitled, "Poloxamer 407 as an Intraperitoneal Barrier Material for the Prevention of Post-Surgical Adhesion Formation and Reformation in Rodent Models for Reproductive Surgery, Obstetrics and Gynecology, volume 1, pages 48-52, 1991, discloses the anti-adhesion properties of poloxamer 407. Poloxamer 407 is a biocompatable polymer, the viscosity of which is dependent upon temperature and concentration in aqueous solutions. The material is a liquid at room temperature and is a solid at body temperature. In one experiment, poloxamer solutions in concentrations ranging from 15-35% were applied to standardized lesions on the uterine horn of hamsters. Significant reduction in post-traumatic adhesion formation was observed following treatment with the poloxamer solutions. In a second experiment, the polymer was used in a paradigm for a typical situation encountered in fertility surgery, that is, the prevention of adhesion reformation after lysis of established adhesions. The effects of applying poloxamer 407 after adhesiotomy in rabbits was compared to controls that had received no treatments. The adhesion reformation was reduced by a poloxamer 407 treatment.
Steinleitner in an article entitled, "New Modalities Under Development for Adhesion Prevention; "Immunomodulatory Agents and Poloxamer Barrier Materials", Gynecologic Surgery and Adhesion Prevention, pages 235-251, 1993 discloses a review of the pathophysiology of peritoneal wound repair that summarizes studies evaluating immunomodulatory agents designed to favorably influence aspects of post surgical healing. Besides describing the physiology of peritoneal repairs, the authors of the studies list a number of immunomodulatory agents used in adhesion prevention such as calcium channel blocking agents and other agents such as pentoxifylline. The authors emphasize the application of barrier materials to effect physical separation of injured viscera stating that it may be the most effective therapy currently available to surgeons. The ideal barrier material should be biocompatible, be absorbable and have a neutral or beneficial effect on the events of peritoneal healing. Further, the barrier material should serve as a local delivery system for pharmacologic anti-adhesion treatments. Poloxamer 407 has been identified as particularly well suited for use in preventing adhesion formation or reformation as a barrier material in infertility surgery.
The Steinleitner review discloses the use of pentoxifylline in preventing the formation of post surgical adhesions. Pentoxifylline is a methylxanthine derivative which improves the flow properties of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, pentoxifylline increases blood flow to the affected microcirculation and enhances tissue oxygenation. Steinleitner et al. used the hamster uterine horn primary injury model and administered doses of 0.1 to 10 mg.backslash.kg subcutaneously at 12 hour intervals. This regimen was found to provide protection against post-traumatic adhesion formation.
While the prior art discloses the use of pentoxifylline and poloxamer 407 separately as agents that may be useful in inhibiting or reducing the formation/reformation of adhesions in the peritoneal cavity for mammals, there is a need for an improved composition that can be applied directly to the body cavity and a process for reducing post surgical adhesion formation/reformation.